Estimated Savings After Stopping Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myeloid Leukemia

Key Points Question What is the estimated population-level financial effect of discontinuing tyrosine kinase inhibitor (TKI) treatment in patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response? Findings In this decision analytical modeling study of the current US population with CML, a microsimulation model was used to estimate future health care spending. The findings indicate that an estimated $50 billion could be saved by eligible patients who attempt to stop TKI therapy. Meaning These findings suggest that attempting to stop TKI therapy could improve quality of life for patients with CML and may result in a large reduction in health care costs.


Introduction
Since the introduction of tyrosine kinase inhibitors (TKIs), care for patients with chronic myeloid leukemia (CML) has radically changed, and survival of patients with CML is now similar to survival in the general population without CML. 1 However, TKIs remain very expensive, resulting in a financial burden on patients and the health care system. 2 For patients with a sustained deep molecular

+ Supplemental content
Author affiliations and article information are listed at the end of this article.response (MR4 or better; BCR::ABL1 Յ 0.01% on the International Scale), attempting discontinuation of TKI therapy is safe.4][5] The Life After Stopping TKIs (LAST) study 6 was the first prospective US-only trial to evaluate TFR; at 3 years, 60.8% sustained discontinuation of TKI therapy.Attempting to discontinue TKI therapy requires additional laboratory tests to monitor molecular response.Herein, we used findings from the LAST study to estimate spending on drugs and testing associated with trying to discontinue TKI therapy among all eligible adult patients in the US.We constructed a model of CML drug and polymerase chain reaction (PCR) costs that account for savings from reduced TKI use during TFR, increased testing during TFR, and increased costs associated with reinitiating TKI treatment after a failed discontinuation attempt.
Herein, we estimate the changes in health care spending after attempting to discontinue TKI therapy among eligible US adults over the next 30 years.

Methods Population
This decision analytical modeling study was approved by the Medical College of Wisconsin Institutional Review Board.We used the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist to guide the development of this model.To estimate the future drug and PCR spending for patients with CML in the US, we accounted for the current population with CML (prevalent cohort) and estimated new cases of CML (incident cohort) expected over time.We created the prevalent cohort based on the population of individuals with CML in 2018 using estimates from the SEER*Explorer interactive website. 7We created the incident cohort by taking the current US population and annually diagnosing individuals with CML based on age and sex incidence rates. 7For those who were not diagnosed, we allowed individuals to die based on age-and sex-specific US mortality tables. 8We aged those not diagnosed with CML and who did not die each year and repeated the process, creating an incidence cohort each year.
Consistent with current clinical practice guidelines, 9 we required patients to have used TKIs for at least 3 years and achieved MR4 for at least 2 years to be eligible to attempt TKI discontinuation.
For the prevalent cohort, we estimated that 30% of patients using a first-generation TKI would be at MR4, and 50% of patients using a second-generation TKI would be at MR4. 10 For the incident cohort, we estimated the time to reach MR4 within 5 years after diagnosis by fitting a parametric time-toevent model for those using a first-or second-generation TKI to match previously published trialbased time-to-MR4 curves. 11If patients were not eligible at year 5, we made the conservative assumption that they would not become eligible; however, some studies find that some patients will reach MR4 after 5 years. 12

Simulation Model
With a 1-month cycle length, we developed a microsimulation model of patients with sustained deep molecular response to compare drug and PCR costs of continuing and attempting to stop TKI therapy.Based on the LAST study and other trials, we assumed that attempting discontinuation with increased monitoring does not result in disease progression or changes in mortality rates.Costs of health care services used were assigned based on current TKI use and associated expected testing. [15]

Use of TKIs
Based on a commercial claims (MarketScan) observational database study, 16 we assumed that 54% of patients start therapy with a second-generation TKI.We estimated the time to TKI therapy discontinuation for patients who attempt discontinuation using parametric time-to-event models.

JAMA Network Open | Hematology
Estimated Savings After Stopping TKI Treatment for Patients With CML Using data from the LAST study, we estimated time-to-event models from discontinuation to reinitiation of treatment.Given the different hazard functions in the early period (within 18 months of discontinuation) and the late period (after 18 months of discontinuation), we fit 2 models.We fit a parametric time-to-event model (exponential, Weibull, and Gompertz) for both periods and selected the model with the best Akaike and Bayesian information criteria.In the early period, we used a Gompertz model, whose hazard can take on different shapes to ensure it matches the underlying data; for the late period, we used the exponential model, which has a constant hazard (eFigures 1 and 2 in Supplement 1 provide a comparison between models and empirical survival estimates that show curves that are very similar to the empirical data).For patients who do not attempt TKI discontinuation because they do not reach MR4, we assumed they were taking a TKI.

Mortality
We used US life tables to estimate a patient's risk of death.We assumed that patients who reach MR4 survive similarly to the general population. 1,17

Costs
After TKI therapy discontinuation, patients are tested for CML recurrence monthly for the first 6 months, bimonthly for the next 18 months, and then every 3 months for the entirety of their lives.For the comparison group, those who never attempted to discontinue TKI therapy are tested every 3 months.We estimated spending associated with first-and second-generation TKIs based on previously published findings using MarketScan (Table ). 18We assumed that the cost of a PCR test was US $144 based on the Medicare laboratory fee schedule. 19

Sensitivity Analysis
Prior research has found that the US population with CML has a risk of death higher than that of the general population. 20While this is not true among those that have reached MR4, as an upper bound, we estimated how doubling the risk of mortality might affect the savings.

Results
The median age at diagnosis was 66 years for men and 65 years for women.We found that the cumulative savings for attempting to discontinue TKI therapy for eligible patients was over $15 billion within 10 years (Figure 1).These savings continued to grow; at 30 years, the estimated savings were over $54 billion.Sensitivity analyses assuming patients' mortality rate was double the national average found savings at $43 billion (Figure 2).

Discussion
In this decision analytical modeling study, we estimate that attempting to discontinue TKI therapy for patients with CML who achieved MR4 could result in considerable savings to the health care system.
Taken with other research, which has found that patients' quality of life improves when they discontinue TKI therapy, 6,21 that patients define a cure as discontinued TKI therapy, 22 and that a patient's disease does not progress even if they have to reinitiate treatment, [3][4][5][6] it is clear that widespread TKI therapy discontinuation is beneficial for eligible patients.The analysis assumed that the mortality rate was twice the national average in the US.Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer:
The content is solely the responsibility of the authors and does not represent the opinion of the NIH.
Data Sharing Statement: See Supplement 2.

Question
What is the estimated population-level financial effect of discontinuing tyrosine kinase inhibitor (TKI) treatment in patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response?Findings In this decision analytical modeling study of the current US population with CML, a microsimulation model was used to estimate future health care spending.The findings indicate that an estimated $50 billion could be saved by eligible patients who attempt to stop TKI therapy.Meaning These findings suggest that attempting to stop TKI therapy could improve quality of life for patients with CML and may result in a large reduction in health care costs.

Figure 1 .Figure 2 .
Figure 1.Estimated Savings Associated With Attempting to Stop Tyrosine Kinase Inhibitor Use Among Patients With Chronic Myeloid Leukemia in Deep Molecular Response

Table . Model Parameters
a Estimated from the Life After Stopping TKIs (LAST) study.
Pharmaceutical Industries Ltd, and Terns Pharmaceuticals Inc and grant funding from Novartis AG and Bristol Myers Squibb outside the submitted work.Dr Deininger reported receiving personal fees and research funding from Blueprint Medicines Corporation, Takeda Pharmaceutical Company Limited, Novartis AG, and Incyte; personal fees from Medscape, Fusion Pharmaceuticals Inc, Sangamo Therapeutics Inc, and DiserSol; and research funding from Sun Pharma Advanced Research Company, the Leukemia & Lymphoma Society, and Pfizer Inc outside the submitted work.Dr Kota reported receiving personal fees from Novartis AG and Pfizer Inc outside the submitted work.Dr Larson reported receiving personal fees from Amgen Inc, ARIAD Pharmaceuticals Inc/Takeda Pharmaceutical Company Ltd, Astellas Pharma, Celgene Corporation/Bristol Myers Squibb, CVS Caremark, Epizyme Inc, ImmunoGen Inc, Jazz Pharmaceuticals Inc, Medpace, MorphoSys AG, Novartis AG, and Servier Laboratories; clinical research support from Astellas Pharma, Celgene Corporation, Cellectis, Daiichi Sankyo Company Ltd, Forty Seven Sciences Inc/Gilead Sciences Inc, Novartis AG, Takeda Pharmaceutical Company Ltd, Bristol Myers Squibb, and Rafael Pharmaceuticals Inc; and royalties from UpToDate outside the submitted work.Dr Mauro reported receiving personal fees and research funding from Novartis Oncology and Bristol Myers Squibb, personal fees from Takeda Pharmaceutical Company Ltd and Pfizer Inc, and research funding from Sun Pharma Advanced Research Company outside the submitted work.Dr Oehler reported receiving grant funding from Pfizer Inc; consulting fees from Novartis AG, Takeda Pharmaceutical Company Ltd, Bristol Myers Squibb, and Ascentage Pharma; and funds for educational outreach for American Society of Clinical Oncology Advantage outside the submitted work.Dr Pinilla-Ibarz reported receiving grant funding from the NIH during the conduct of the study and personal fees from Janssen Global Services LLC, AbbVie Inc, AstraZeneca, BeiGene, Eli Lilly and Company, Novartis AG, Pfizer Inc, and Takeda Pharmaceutical Company Ltd outside the submitted work.Dr Radich reported receiving grant funding from the National Cancer Institute during the conduct of the study and personal fees from Novartis AG, Bristol Myers Squibb, Takeda Pharmaceutical Company Ltd, Amgen Inc, Cepheid, and Genentech Inc outside the submitted work.Dr Shah reported receiving grant funding from Bristol Myers Squibb outside the submitted work.Dr Thompson reported receiving grants from Bristol Myers Squibb and Novartis AG outside the submitted work.Dr Flynn reported receiving grant funding from Novartis AG and the NIH and personal fees Pfizer Inc and Inhibikase Therapeutics Inc, outside the submitted work.No other disclosures were reported.This work was supported by grant R01 CA184798 from the National Cancer Institute at the NIH (Drs Atallah and Flynn).